Arastad 20

Rx

Indications:

Arastad 20 is indicated for the treatment of adult patients (18 years of age and older) with:

• Active rheumatoid arthritis as a “disease-modifying antirheumatic drug” (DMARD)
• Active psoriatic arthritis.

Usage:

• The treatment should be initiated and supervised by specialists experienced in the treatment of rheumatoid arthritis and psoriatic arthritis.
• Alanine aminotransferase (ALT) or serum glutamopyruvate transferase (SGPT) and a complete blood cell count, including a differential white blood cell count and a platelet count, must be checked simultaneously and with the same frequency:
  + before initiation of leflunomide,
  + every 2 weeks during the first 6 months of treatment, and
  + every 8 weeks thereafter.
  In rheumatoid arthritis: Loading dose of 100 mg once daily for 3 days. Omission of the loading dose may decrease the risk of adverse events. The recommended maintenance dose is leflunomide 10 mg to 20 mg once daily depending on the severity (activity) of the disease.
  In psoriatic arthritis: Loading dose of 100 mg once daily for 3 days. The recommended maintenance dose is leflunomide 20 mg once daily.
  The therapeutic effect usually starts after 4 to 6 weeks and may further improve up to 4 to 6 months. There is no dose adjustment recommended in patients with mild renal insufficiency.
  No dose adjustment is required in patients above 65 years of age.

Administration:
Arastad 20 is administered orally without regard to meals.

• Hypersensitivity (especially previous Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) to the active substance, to the principal active metabolite teriflunomide or to any of the excipients.
• Patients with impairment of liver function.
• Patients with severe immunodeficiency states, e.g. AIDS.
• Patients with significantly impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia due to causes other than rheumatoid or psoriatic arthritis.
• Patients with serious infections.
• Patients with moderate to severe renal insufficiency, because insufficient clinical experience is available in this patient group.
• Patients with severe hypoproteinaemia, e.g. in nephrotic syndrome.
• Pregnant women, or women of childbearing potential who are not using reliable contraception during treatment with leflunomide and thereafter as long as the plasma levels of the active metabolite are above 0.02 mg/L. Pregnancy must be excluded before start of treatment with leflunomide.
• Breast-feeding women.
• Patients below 18 years since efficacy and safety in juvenile rheumatoid arthritis (JRA) have not been established.

Common:

• Mild increase in blood pressure.
• Leucopenia
• Colitis including microscopic colitis such as lymphocytic colitis, collagenous colitis, diarrhoea, nausea, vomiting, oral mucosal disorders (e.g., aphthous stomatitis, mouth ulceration), abdominal pain.
• Elevation of liver parameters.
• Anorexia, weight loss (usually insignificant), asthenia.
• Mild allergic reactions.
• Increased hair loss, eczema, rash (including maculopapular rash), pruritus, dry skin.
• Tenosynovitis.
• Paraesthesia, headache, dizziness, peripheral neuropathy.

• Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) is not advisable.
• The active metabolite of leflunomide, A771726, has a long half-life, usually 1 to 4 weeks. Serious undesirable effects might occur (e.g. hepatotoxicity, haematotoxicity or allergic reactions), even if the treatment with leflunomide has been stopped. Therefore, when such toxicities occur or if for any other reason A771726 needs to be cleared rapidly from the body, the washout procedure has to be followed.
• Rare cases of severe liver injury, including cases with fatal outcome, have been reported during treatment with leflunomide. Most of the cases occurred within the first 6 months of treatment. Co-treatment with other hepatotoxic medicinal products was frequently present. It is considered essential that monitoring recommendations are strictly adhered to.
• ALT (SGPT) must be checked before initiation of leflunomide and at the same frequency as the complete blood cell count (every two weeks) during the first six months of treatment and every 8 weeks thereafter.
• It is recommended that monitoring of liver enzymes be maintained after discontinuation of leflunomide treatment, until liver enzyme levels have normalised. Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be avoided during treatment with leflunomide.
• Arastad 20 is contraindicated in patients with severe hypoproteinaemia or impairment of liver function.
• A complete blood cell count, including differential white blood cell count and platelets, must be performed before start of leflunomide treatment as well as every 2 weeks for the first 6 months of treatment and every 8 weeks thereafter.
• In patients with pre-existing anaemia, leucopenia, and/or thrombocytopenia as well as in patients with impaired bone marrow function or those at risk of bone marrow suppression, the risk of haematological disorders is increased. If such effects occur, a washout to reduce plasma levels of A771726 should be considered.
• In case of severe haematological reactions, including pancytopenia, Arastad 20 and any concomitant myelosuppressive treatment must be discontinued and a leflunomide washout procedure initiated.
  The use of leflunomide with antimalarials used in rheumatic diseases (e.g. chloroquine and hydroxychloroquine), intramuscular or oral gold, D-penicillamine, azathioprine and other immunosuppressive agents including tumour necrosis factor alpha-inhibitors has not been adequately studied up to now in randomised trials (with the exception of methotrexate). The risk associated with combination therapy, in particular in long-term treatment, is unknown. Since such therapy can lead to additive or even synergistic toxicity (e.g. hepato- or haematotoxicity), combination with another DMARD (e.g. methotrexate) is not advisable.
• Co-administration of teriflunomide with leflunomide is not recommended, as leflunomide is the parent compound of teriflunomide.
• As leflunomide has a long persistence in the body, a switching to another DMARD (e.g. methotrexate) without performing the washout procedure may raise the possibility of additive risks even for a long time after the switching (i.e. kinetic interaction, organ toxicity).
• Similarly, recent treatment with hepatotoxic or haematotoxic medicinal products (e.g. methotrexate) may result in increased side effects; therefore, the initiation of leflunomide treatment has to carefully be considered regarding these benefit/risk aspects and closer monitoring is recommended in the initial phase after switching.
• In case of ulcerative stomatitis, leflunomide administration should be discontinued.
• Very rare cases of Stevens-Jonhson syndrome or toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in patients treated with leflunomide. As soon as skin and/or mucosal reactions are observed which raise the suspicion of such severe reactions, Arastad 20 and any other possibly associated treatment must be discontinued, and a leflunomide washout procedure initiated immediately. A complete washout is essential in such cases. In such cases re-exposure to leflunomide is contraindicated.
• Pustular psoriasis and worsening of psoriasis have been reported after the use of leflunomide. Treatment withdrawal may be considered taking into account patient’s disease and past history.
• It is known that medicinal products with immunosuppressive properties – like leflunomide – may cause patients to be more susceptible to infections, including opportunistic infections. Infections may be more severe in nature and may, therefore, require early and vigorous treatment. In the event that severe, uncontrolled infections occur, it may be necessary to interrupt leflunomide treatment and administer a washout procedure as described below.
• Rare cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving leflunomide among other immunosuppressants.
• Before starting treatment, all patients should be evaluated for active and inactive (“latent”) tuberculosis, as per local recommendations. This can include medical history, possible previous contact with tuberculosis, and/or appropriate screening such as lung X-ray, tuberculin test and/or interferon-gamma release assay, as applicable. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised. Patients with a history of tuberculosis should be carefully monitored because of the possibility of reactivation of the infection.
• Interstitial lung disease, as well as rare cases of pulmonary hypertension have been reported during treatment with leflunomide. The risk of their occurrence can be increased in patients with a history of interstitial lung disease. Interstitial lung disease is a potentially fatal disorder, which may occur acutely during therapy. Pulmonary symptoms, such as cough and dyspnoea, may be a reason for discontinuation of the therapy and for further investigation, as appropriate.
• Cases of peripheral neuropathy have been reported in patients receiving leflunomide. Most patients improved after discontinuation of leflunomide. However there was a wide variability in final outcome, i.e. in some patients the neuropathy resolved and some patients had persistent symptoms.
• Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking Arastad 20 develops a peripheral neuropathy, consider discontinuing Arastad 20 therapy and performing the drug elimination procedure.
• Colitis, including microscopic colitis has been reported in patients treated with leflunomide. In patients on leflunomide treatment presenting unexplained chronic diarrhoea appropriate diagnostic procedures should be performed.
• Blood pressure must be checked before the start of leflunomide treatment and periodically thereafter.
• Male patients should be aware of the possible male-mediated foetal toxicity. Reliable contraception during treatment with leflunomide should also be guaranteed.
• There are no specific data on the risk of male-mediated foetal toxicity. However, animal studies to evaluate this specific risk have not been conducted. To minimise any possible risk, men wishing to father a child should consider discontinuing use of leflunomide and taking cholestyramine 8 g 3 times daily for 11 days or 50 g of activated powdered charcoal 4 times daily for 11 days.
• Arastad 20 contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
• Patients should be aware of how they react to drug before driving or operating machinery.